Association of myostatin, a cytokine released by muscle, with inflammation in rheumatoid arthritis

Instituto Mexicano del Seguro Social, Fondo de Investigacion en Salud, FIS/IMSS/PROT/MD16/1565Supplemental Digital Content is available in the text Myostatin is a cytokine produced and released by myocytes that might have an outstanding role not only in muscle wasting during cachexia but also in inflammation. Herein we explore the association between myostatin levels and inflammatory parameters in rheumatoid arthritis (RA). One hundred twenty-seven women without rheumatic diseases and 84 women with a diagnosis of RA were assessed in a cross-sectional study. Outcomes reflecting the activity of the arthritis including Disease Activity Score (DAS28-ESR) and impairment in functioning by the Health Assessment Questionnaire-Disability Index were assessed in RA. We obtained Skeletal muscle mass index (SMI), fat-free mass index (FFMI), and fat mass index using dual-energy x-ray absorptiometry. Serum myostatin was determined by enzyme-linked immunosorbent assay. Myostatin levels were correlated with disease activity and parameters of muscle mass. The SMI was lower and concentration of myostatin was higher in RA patients than in controls (P = .008 and P < .001, respectively). Myostatin significantly positively correlated with C-reactive protein (rho = 0.48, P < .001), erythrocyte sedimentation rate (rho = 0.28, P = .009), and DAS28-ESR (rho = 0.22, P = .04), and negatively correlated with SMI (rho = −0.29, P = .008), (FFMI) (rho = −0.24, P = .027). In the multivariate logistic regression analysis, levels of myostatin remained associated with disease activity in RA (P = .027). In our study, myostatin was associated with disease activity in RA patients, suggesting a mechanistic link between myostatin, muscle wasting and inflammation in RA

Diversidad, rareza, evolución y conservación de la flora endémica de las Islas Canarias

The endemic vascular flora of the Canary Islands comprises over 680, taxa collectively accounting for more than 50% of the total native flora. To investigate geographical patterns of diversity within the endemic flora, distribution data from published sources together with other field observation and herbarium data were used to compile a data matrix comprising the distributions of ca. 90% of endemic taxa scored on a 10 × 10km UTM grid. WORLDMAP was then used to investigate patterns of endemic diversity, range size rarity (a measure of endemicity), phylogenetic diversity and threatened taxon richness. Endemic taxon richness was found to be highly heterogeneous across the archipelago, with cells containing between one and 139 taxa each (0.05-22.82% of endemic diversity). Patterns of variation in range size rarity and phylogenetic diversity were found to be largely congruent with endemic diversity, although some cells exhibited markedly higher range size rarity scores than would be predicted by their endemic diversity scores. In contrast, the pattern of endangered taxon richness across the archipelago differed markedly from endemic taxon richness. Many cells in Lanzarote, Fuerteventura and Gran Canaria exhibit higher endangered taxon richness scores than would be predicted from their endemic richness scores whereas in Tenerife, El Hierro, La Palma and La Gomera, the converse is generally true. The implications of the results both for understanding the evolution of Canary Island endemic diversity and for the conservation of the region’s unique and vulnerable flora are considered.La flora vascular endémica de las Islas Canarias comprende unos 680 táxones, lo que viene a representar más del 50% de la flora nativa. Con objeto de investigar patrones geográficos de diversidad en la flora endémica, se recopilaron los datos publicados que, junto con otras observaciones de campo y datos de herbario, sirvieron para completar una matriz de datos que abarca la distribución de cerca del 90% de los táxones endémicos usando cuadrículas UTM de10 × 10 km. A continuación, se utilizó el programa WORLDMAP para investigar los patrones de diversidad de los endemismos, el rango del grado de rareza (una medida de endemicidad), la diversidad filogenética y la riqueza en táxones amenazados. Se observó que la riqueza en endemismos es muy heterogénea a lo largo del archipiélago, con unos valores por cuadrícula que oscilan entre 1 y 139 táxones (0,05-22,82% de la diversidad de táxones endémicos). Los patrones de variación del rango del grado de la rareza y la diversidad filogenética resultaron ser en gran parte congruentes con la diversidad en endemismos, aunque algunas cuadrículas mostraron valores mucho más altos de rareza de los que podían ser predichos dada su diversidad de endemismos. En contraste, los patrones de riqueza en especies amenazadas en el archipiélago difirieron marcadamente de la riqueza en táxones endémicos. Muchas cuadrículas de Lanzarote, Fuerteventura y Gran Canaria mostraron valores más altos de riqueza en especies amenazadas que las que pudieran ser predichas sobre la base de su riqueza en táxones endémicos, mientras que en Tenerife, El Hierro y La Gomera la regla fue generalmente lo contrario. Se consideran las implicaciones que estos resultados suponen para la comprensión de la evolución de la diversidad de endemismos canaria y para la conservación de su singular y vulnerable flora

Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-gamma-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-gamma expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-gamma production, but also the protective function of iNKT cells in arthritis

Living at the edge: home range patterns of the Buraiga Chimpanzee Community, Kibale National Park, Uganda

Data on space-use patterns are essential for understanding species ecology and conservation. Individual chimpanzee communities are known to vary in home range size and habitat use dynamics, reflecting site-specific strategies to differences in resource availability on different landscapes. Here we present home range estimates for the Buraiga chimpanzees of Kibale National Park, Uganda, a community of eastern chimpanzees (Pan troglodytes schweinfurthii) living within the largest remaining population fragment in Uganda. The Buraiga chimpanzees are currently undergoing habituation for research and tourism under the direction of the Uganda Wildlife Authority (UWA). We analyzed 15 months of GPS data (August 2019 – March 2020, and January – July 2022), calculating overall and seasonal home range and core area estimates with two methods, minimum convex polygon (MCP) and kernel density estimates (KDE). Home range was estimated to cover an area of 15.77 km2 (95% KDE), and 24.90 km2 (100% MCP). Additionally, we found that 15.82% of the Buraiga chimpanzee’s home range overlaps with community-managed land, primarily the Kanyanchu Swamp corridor and adjacent agricultural land. Seasonally, we found that Buraiga chimpanzees used a larger area during dry season months, compared with rainy season months. Documenting how great ape populations utilize increasingly anthropogenically influenced landscapes is important in order to facilitate long-term survival in the face of climate change, habitat fragmentation, and other ongoing threats

Direct TLR2 Signaling Is Critical for NK Cell Activation and Function in Response to Vaccinia Viral Infection

Natural killer (NK) cells play an essential role in innate immune control of poxviral infections in vivo. However, the mechanism(s) underlying NK cell activation and function in response to poxviruses remains poorly understood. In a mouse model of infection with vaccinia virus (VV), the most studied member of the poxvirus family, we identified that the Toll-like receptor (TLR) 2-myeloid differentiating factor 88 (MyD88) pathway was critical for the activation of NK cells and the control of VV infection in vivo. We further showed that TLR2 signaling on NK cells, but not on accessory cells such as dendritic cells (DCs), was necessary for NK cell activation and that this intrinsic TLR2-MyD88 signaling pathway was required for NK cell activation and played a critical role in the control of VV infection in vivo. In addition, we showed that the activating receptor NKG2D was also important for efficient NK activation and function, as well as recognition of VV-infected targets. We further demonstrated that VV could directly activate NK cells via TLR2 in the presence of cytokines in vitro and TLR2-MyD88-dependent activation of NK cells by VV was mediated through the phosphatidylinositol 3-kinase (PI3K)-extracellular signal-regulated kinase (ERK) pathway. Taken together, these results represent the first evidence that intrinsic TLR signaling is critical for NK cell activation and function in the control of a viral infection in vivo, indicate that multiple pathways are required for efficient NK cell activation and function in response to VV infection, and may provide important insights into the design of effective strategies to combat poxviral infections

Human Herpesvirus 8 (HHV8) Sequentially Shapes the NK Cell Repertoire during the Course of Asymptomatic Infection and Kaposi Sarcoma

The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells

Inflammasome-dependent Pyroptosis and IL-18 Protect against Burkholderia pseudomallei Lung Infection while IL-1β Is Deleterious

Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and other cell types and causes melioidosis. The interaction of B. pseudomallei with the inflammasome and the role of pyroptosis, IL-1β, and IL-18 during melioidosis have not been investigated in detail. Here we show that the Nod-like receptors (NLR) NLRP3 and NLRC4 differentially regulate pyroptosis and production of IL-1β and IL-18 and are critical for inflammasome-mediated resistance to melioidosis. In vitro production of IL-1β by macrophages or dendritic cells infected with B. pseudomallei was dependent on NLRC4 and NLRP3 while pyroptosis required only NLRC4. Mice deficient in the inflammasome components ASC, caspase-1, NLRC4, and NLRP3, were dramatically more susceptible to lung infection with B. pseudomallei than WT mice. The heightened susceptibility of Nlrp3-/- mice was due to decreased production of IL-18 and IL-1β. In contrast, Nlrc4-/- mice produced IL-1β and IL-18 in higher amount than WT mice and their high susceptibility was due to decreased pyroptosis and consequently higher bacterial burdens. Analyses of IL-18-deficient mice revealed that IL-18 is essential for survival primarily because of its ability to induce IFNγ production. In contrast, studies using IL-1RI-deficient mice or WT mice treated with either IL-1β or IL-1 receptor agonist revealed that IL-1β has deleterious effects during melioidosis. The detrimental role of IL-1β appeared to be due, in part, to excessive recruitment of neutrophils to the lung. Because neutrophils do not express NLRC4 and therefore fail to undergo pyroptosis, they may be permissive to B. pseudomallei intracellular growth. Administration of neutrophil-recruitment inhibitors IL-1ra or the CXCR2 neutrophil chemokine receptor antagonist antileukinate protected Nlrc4-/- mice from lethal doses of B. pseudomallei and decreased systemic dissemination of bacteria. Thus, the NLRP3 and NLRC4 inflammasomes have non-redundant protective roles in melioidosis: NLRC4 regulates pyroptosis while NLRP3 regulates production of protective IL-18 and deleterious IL-1β

Seed Germination Strategies of Mediterranean Halophytes Under Saline Condition

The study of the ecological strategies adopted by seed plants to ensure their success in different environments is closely related to germination ecology. This implies a careful knowledge of ecophysiology of seeds and, therefore, also of interaction between plants and the complexity of external factors. In particular, the environmental conditions of the area where a plant grows and produces seeds represent the main factors that influence successful seedling establishment. The physical-chemical features of habitats, and therefore their heterogeneity, affect the behavior of seeds in different ways. In addition to the timing of seed production, they can induce or terminate dormancy and/or germination and influence the germination pattern of different seeds in the same plant and so the composition and dispersal of soil seed banks. Salinity is a major abiotic stress affecting growth and plant productivity worldwide, constituting one of the main topics of study in the field of plant physiology. Halophytes are the plants that have the availability to survive and develop in different types of saline habitats. In this chapter, we consider some examples to illustrate the main adaptive strategies used by the seeds of halophytes on ecophysiological perspectives to survive in habitats affected by high levels of salinity. The focus is on the species that live in the brackish or salt coastal areas of the Mediterranean Basin. On these environments, the salt stress may act synergistically with intense anthropic pressure, generating profound alterations in the ecosystem and threatening the survival of the plant species very sensitive to the effects of climate change also. The results show the main diverse strategies, such as dormancy cycling, seed heteromorphism, and recovery capacity, from saline shock, favoring the chances of seed survival. The interaction between temperature and salinity during germination was also discussed assessing its crucial role as an ecological strategy

Primary intestinal lymphangiectasia (Waldmann's disease)

Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool α1-antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum) or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other inconsistently effective treatments have been proposed for PIL patients, such as antiplasmin, octreotide or corticosteroids. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. PIL outcome may be severe even life-threatening when malignant complications or serous effusion(s) occur